Angiogenesis is the formation of new capillaries from pre-existing capillaries. This process is most prevalent during development and growth of an organism, including humans. In adults, angiogenesis is mostly associated with wound healing, endometrial remodeling and the menstrual cycle. Pathogenic angiogenesis has been implicated in many different diseases, such as cancer, diabetic retinopathy, psoriasis, macular degeneration, rheumatoid arthritis, etc. Recent studies have reported identification of several endogenous inhibitors of angiogenesis, such as thrombopondin, angiostatin, endostatin and tumstatin. These endogenous inhibitors function in opposition to several pro-angiogenic factors such as VEGF, FGF, etc., and are thought to provide the regulatory balance for angiogenesis. In this grant proposal, we will investigate the mechanism behind the action of tumstatin, an endogenous inhibitor of angiogenesis. The focus of this grant is to better understand the need for the human body to generate endogenous inhibitors of angiogenesis. We hope to answer questions such as, what happens when endogenous inhibitors are genetically removed from the body? How do these inhibitors work? Why are they non-toxic and specific to dividing endothelial cells that are in the process of making new capillaries around tumor ceils? What is the molecular message sent by tumstatin to a dividing endothelial cell? Successful completion of the experiments proposed in this grant application will provide valuable insight into how these endogenous inhibitors function and their potential use as anti-tumor agents in the clinic.